Project Summary Recent studies in animal models have suggested a critical role for cerebrospinal fluid (CSF) / Interstitial fluid (ISF) flux through cerebral parenchyma for removal of byproducts of cellular metabolism and hence in maintaining the health of the brain. An important finding is that this interstitial fluid compartment shows dramatic increases during sleep, which points to a potentially important mechanism for sleep to maintain both acute homeostasis and long-term cerebral health. The central goal of these studies is to develop a sensitive measure of changes in cerebral ISF that may be a biomarker of sleep effectiveness. A key unanswered question still remains; How prevalent are these CSF/ISF pathways (and postulated pathophysiological sequelae) in the human brain? This exploratory work aims to establish the sensitivity and reproducibility of diffusion MRI changes as a non-invasive neuroimaging assessment of CSF/ISF shifts in humans during natural sleep and sedation. The outcome of these studies will be a new technique for characterization of normal sleep physiology, and for monitoring sleep disorders, based on sleep-dependent changes in CSF/ISF flux. It also offers a novel window into other cerebral insults that may disrupt the tissue microenvironment and thus may impair sleep effectiveness.